Regulatory Decision Summary for Cresemba
The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.
Type of submission:
What was the purpose of this submission?
The main purpose of this New Drug Submission was to seek marketing authorization of a new antifungal agent Cresemba (isavuconazole) for the treatment of invasive aspergillosis and invasive mucormycosis in adult patients.
Why was the decision issued?
Health Canada considers that the benefit/risk profile of Cresemba (isavuconazole) is favorable for use in adult patients infected with invasive aspergillosis and invasive mucormycosis. The proposed indications of isavuconazole for invasive aspergillosis and invasive mucormycosis have been supported by non-clinical and clinical studies. Each indication has been supported by a pivotal phase 3 clinical trial respectively.
The majority of patients infected with invasive fungal disease caused by Aspergillus or mucorales species in these trials were immunocompromised with underlying conditions including hematological malignancy, neutropenia post-chemotherapy, graft-versus-host disease, and hematopoietic stem cell transplant. In addition, the majority of invasive mucormycosis patients had pulmonary disease involvement and some with other organs involvement. The median treatment duration was longer in the treatment of invasive mucormycosis than that in invasive aspergillosis.
Treatment of invasive aspergillosis was supported by a phase 3 non-inferiority study. Patients with proven or probable invasive fungal disease caused by Aspergillus species dosed with isavuconazole demonstrated non-inferiority to the voriconazole-treated control group in all-cause mortality through Day 42 (18.6% vs. 20.2% respectively). Similar results showed through Day 84. The overall success rates in the isavuconazole group of mycologically evaluable patient population also showed non-inferiority to voriconazole control.
Treatment efficacy of invasive mucormycosis with isavuconazole was demonstrated with an open-label and non-comparative study. For patients with invasive mucormycosis caused by Mucorales species, the all-cause mortality through Day 42 and 84 were 38% and 43% respectively. The all-cause mortality rates in patients dosed as primary therapy were similar to those refractory or intolerant to prior antifungal treatment at these time points. Similar results were observed with the overall response rates at end of treatment.
Cresemba use was generally safe and well-tolerated. The most frequently reported treatment-emergent adverse reactions among patients with Cresemba were nausea, vomiting, diarrhea, headache, elevated liver chemistry tests, and hypokalemia. The adverse reactions that most often led to permanent discontinuation of Cresemba during the clinical trials were confusional state, acute renal failure, increased blood bilirubin, convulsion, and dyspnea. Most common serious adverse reactions excluding death were febrile neutropenia, respiratory failure, septic shock and pyrexia. Deaths regardless of causes happened with a higher rate in patients with mucormycosis than those with aspergillosis. Most deaths were thought to be associated with progression of fungal disease or underlying conditions. These observations have been appropriately worded in Warnings and Precautions section of the Product Monograph.
The clinical harms/uncertainties associated with the use of Cresemba have been identified as following: limited clinical experience in invasive mucormycosis and long term dosing (> 6 months); potential risks in pregnant women and breast-feeding mother; drug-drug interactions with strong cytochrome p450 3A4 inhibitors and strong inducers; risks of cardiac adverse events in high risk patients; and risks of liver enzymes elevation events. These can be managed by active clinical monitoring and other mitigation strategies.
Based on the overall non-clinical and clinical information, Health Canada considers that the anticipated benefits of Cresemba outweigh the potential risks of the product when used as directed in the recommended Product Monograph.
Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations.